Division of Medical Oncology, Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado 80045, USA.
J Thorac Oncol. 2012 Sep;7(9):1440-8. doi: 10.1097/JTO.0b013e318260deaa.
Pemetrexed-based chemotherapy represents the standard of care in first-line treatment of advanced malignant pleural mesothelioma (MPM). However, there are no established predictors of clinical benefit. Pemetrexed inhibits multiple enzymes involved in pyrimidine and purine synthesis, but the main target is thymidylate synthase (TS). After cellular uptake pemetrexed is converted into more effective polyglutamated forms by folylpoly-γ-glutamate synthetase (FPGS). We hypothesized that FPGS and TS protein expressions are associated with clinical outcome after pemetrexed-based chemotherapy.
Pretreatment tumor samples from 84 patients with histologically confirmed MPM, who received pemetrexed combined with platinum (79 of 84) or single-agent pemetrexed (5 of 84) as first-line treatment, were retrospectively analyzed. FPGS and TS protein expressions were semiquantitatively assessed by using the Hybrid (H)-scoring system (range, 0-300). H-scores were correlated with radiological response according to modified Response Evaluation Criteria in Solid Tumors, progression-free survival (PFS) and overall survival (OS).
Median H-score of the entire cohort was 230 for FPGS (range, 100-300), and 210 for TS (range, 100-300). High FPGS protein expression was significantly associated with longer PFS (pCOX = 0.0337), better objective tumor response (partial response versus stable disease + progressive disease; pKW = 0.003), and improved disease-control rate (partial response + stable disease versus progressive disease; pKW = 0.0208), but not with OS. In addition, high TS protein expression was associated with progressive disease under pemetrexed-based therapy (p = 0.0383), and shorter OS (pCOX = 0.0071), but no association with PFS was observed.
FPGS and TS expressions were associated with clinical response and outcome to pemetrexed-based first-line chemotherapy in MPM. Prospective evaluation of FPGS and TS expressions and their prognostic/predictive power in MPM patients is warranted.
培美曲塞为基础的化疗是治疗晚期恶性胸膜间皮瘤（MPM）的一线标准治疗方法。然而，目前还没有明确的临床获益预测因素。培美曲塞抑制嘧啶和嘌呤合成中涉及的多种酶，但主要靶标是胸苷酸合酶（TS）。培美曲塞进入细胞后，被叶酸多聚γ-谷氨酸合成酶（FPGS）转化为更有效的多聚谷氨酸形式。我们假设 FPGS 和 TS 蛋白表达与培美曲塞为基础化疗后的临床结局相关。
回顾性分析了 84 例经组织学证实的 MPM 患者的预处理肿瘤样本，这些患者接受培美曲塞联合铂类（84 例中的 79 例）或单药培美曲塞（84 例中的 5 例）作为一线治疗。使用 Hybrid（H）评分系统（范围为 0-300）半定量评估 FPGS 和 TS 蛋白表达。根据实体瘤反应评价标准（Response Evaluation Criteria in Solid Tumors，RECIST），将 H 评分与影像学反应、无进展生存期（progression-free survival，PFS）和总生存期（overall survival，OS）相关联。
整个队列的中位 FPGS H 评分（范围，100-300）为 230，TS H 评分（范围，100-300）为 210。高 FPGS 蛋白表达与较长的 PFS（pCOX = 0.0337）、更好的客观肿瘤反应（部分缓解与稳定疾病+进展疾病；pKW = 0.003）和提高疾病控制率（部分缓解+稳定疾病与进展疾病；pKW = 0.0208）显著相关，但与 OS 无关。此外，高 TS 蛋白表达与培美曲塞为基础治疗下的疾病进展相关（p = 0.0383），且 OS 更短（pCOX = 0.0071），但与 PFS 无相关性。
FPGS 和 TS 的表达与培美曲塞为基础一线化疗在 MPM 中的临床反应和结局相关。需要前瞻性评估 FPGS 和 TS 表达及其在 MPM 患者中的预后/预测能力。
